title: Bradykinin B₂ receptors increase hippocampal excitability and susceptibility to seizures in mice.
abstract: Bradykinin (BK) and its receptors (B1 and B2) may exert a role in the pathophysiology of certain CNS diseases, including epilepsy. In healthy tissues, B2 receptors are constitutively and widely expressed and B1 receptors are absent or expressed at very low levels, but both receptors, particularly B1, are up-regulated under many pathological conditions. Available data support the notion that up-regulation of B1 receptors in brain areas like the amygdala, hippocampus and entorhinal cortex favors the development and maintenance of an epileptic condition. The role of B2 receptors, instead, is still unclear. In this study, we used two different models to investigate the susceptibility to seizures of B1 knockout (KO) and B2 KO mice. We found that B1 KO are more susceptible to seizures compared with wild-type (WT) mice, and that this may depend on B2 receptors, in that (i) B2 receptors are overexpressed in limbic areas of B1 KO mice, including the hippocampus and the piriform cortex; (ii) hippocampal slices prepared from B1 KO mice are more excitable than those prepared from WT controls, and this phenomenon is B2 receptor-dependent, being abolished by B2 antagonists; (iii) kainate seizure severity is attenuated by pretreatment with a non-peptide B2 antagonist in WT and (more effectively) in B1 KO mice. These data highlight the possibility that B2 receptors may have a role in the responsiveness to epileptogenic insults and/or in the early period of epileptogenesis, that is, in the onset of the molecular and cellular events that lead to the transformation of a normal brain into an epileptic one.
authors.affiliation: Department of Medical Sciences, Section of Pharmacology and Neuroscience Center, University of Ferrara, Ferrara, Italy; National Institute of Neuroscience, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Rodi
authors.affiliation: Department of Medical Sciences, Section of Pharmacology and Neuroscience Center, University of Ferrara, Ferrara, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Buzzi
authors.affiliation: Department of Medical Sciences, Section of Pharmacology and Neuroscience Center, University of Ferrara, Ferrara, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Barbieri
authors.affiliation: Department of Medical Sciences, Section of Pharmacology and Neuroscience Center, University of Ferrara, Ferrara, Italy; National Institute of Neuroscience, Italy; Tecnopolo di Ferrara, Laboratorio per le Tecnologie delle Terapie Avanzate (LTTA), Ferrara, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Zucchini
authors.affiliation: Department of Medical Sciences, Section of Pharmacology and Neuroscience Center, University of Ferrara, Ferrara, Italy; National Institute of Neuroscience, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Verlengia
authors.affiliation: Department of Medical Sciences, Section of Pharmacology and Neuroscience Center, University of Ferrara, Ferrara, Italy; National Institute of Neuroscience, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Binaschi
authors.affiliation: Department of Medical Sciences, Section of Pharmacology and Neuroscience Center, University of Ferrara, Ferrara, Italy; National Institute of Neuroscience, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Regoli
authors.affiliation: Department of Surgery, Anesthesiology and Radiology, Section of Nuclear Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Boschi
authors.affiliation: Department of Physiology, Faculty of Medicine, Université de Montréal, Montreal, QC H3C 3J7, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Ongali
authors.affiliation: Department of Physiology, Faculty of Medicine, Université de Montréal, Montreal, QC H3C 3J7, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Couture
authors.affiliation: Department of Medical Sciences, Section of Pharmacology and Neuroscience Center, University of Ferrara, Ferrara, Italy; National Institute of Neuroscience, Italy; Tecnopolo di Ferrara, Laboratorio per le Tecnologie delle Terapie Avanzate (LTTA), Ferrara, Italy. Electronic address: michele.simonato@unife.it.
authors.forename: M
authors.initials: M
authors.lastname: Simonato
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000378:metabolism; D065169:Bradykinin B1 Receptor Antagonists / Q000494:pharmacology; D065094:Bradykinin B2 Receptor Antagonists / Q000494:pharmacology; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D007608:Kainic Acid / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D066195:Piriform Cortex / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D043783:Receptor, Bradykinin B1 / Q000172:deficiency / Q000378:metabolism*; D043782:Receptor, Bradykinin B2 / Q000172:deficiency / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*
chemical_list: D065169:Bradykinin B1 Receptor Antagonists; D065094:Bradykinin B2 Receptor Antagonists; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D001920:Bradykinin; D007608:Kainic Acid
keywords: autoradiography; electrophysiology; epilepsy; kainate; kindling